Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial

Summary Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We a...

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Published in:The lancet oncology 2015-10, Vol.16 (13), p.1324-1334
Main Authors: Le Tourneau, Christophe, Dr, Delord, Jean-Pierre, Prof, Gonçalves, Anthony, Prof, Gavoille, Céline, MD, Dubot, Coraline, MD, Isambert, Nicolas, MD, Campone, Mario, Prof, Trédan, Olivier, MD, Massiani, Marie-Ange, MD, Mauborgne, Cécile, MSc, Armanet, Sebastien, MSc, Servant, Nicolas, PhD, Bièche, Ivan, PhD, Bernard, Virginie, PhD, Gentien, David, PhD, Jezequel, Pascal, MD, Attignon, Valéry, PhD, Boyault, Sandrine, PhD, Vincent-Salomon, Anne, MD, Servois, Vincent, MD, Sablin, Marie-Paule, MD, Kamal, Maud, PhD, Paoletti, Xavier, PhD
Format: Article
Language:English
Subjects:
Aged
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Biopsy
Cancer therapies
Clinical trials
Cytotoxicity
Disease Progression
Disease-Free Survival
Female
France
Gene Expression Profiling
Genetic Predisposition to Disease
Hematology, Oncology and Palliative Medicine
Histology
Humans
Intention to Treat Analysis
Kaplan-Meier Estimate
Life Sciences
Male
Metastasis
Middle Aged
Molecular Diagnostic Techniques
Molecular Targeted Therapy - adverse effects
Neoplasm Metastasis
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - mortality
Neoplasms - pathology
Neutropenia
Off-Label Use
Ovarian cancer
Patient Selection
Phenotype
Precision Medicine
Predictive Value of Tests
Proportional Hazards Models
Risk Factors
Signal Transduction - drug effects
Time Factors
Treatment Outcome
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Summary:Summary Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. Methods The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT01771458. Findings Between Oct 4,
ISSN:1470-2045
1474-5488
DOI:10.1016/S1470-2045(15)00188-6